γ-Secretase is a complex protein (aspartate protease) comprising presenilin, nicastrin, Aph-1 and Pen-2 as basic components. Presenilin is the catalytic domain; presenilin gene has been identified as a causative gene for familial Alzheimer's disease (AD). γ-Secretase acts on single-pass transmembrane proteins as its substrates. As most representative substrates thereof, amyloid precursor protein (APP) and Notch are known. When cleaved by β-secretase at β-site and by γ-secretase at γ-site, APP produces amyloid β protein (Aβ). The thus-produced Aβ is classified into peptides with different lengths depending on the cleavage site in the amino acid sequence (C-terminal side). Of these peptides, Aβ42 which is strongly hydrophobic and ready to aggregate (ready to take the β-sheet structure) exhibits neurotoxicity. It has been considered that this phenomenon may be the major cause of Alzheimer's disease. Recently, however, a report has been made that presenilin 1 (PS1) and presenilin 2 (PS2) double-knockout mice capable of producing no Aβ show AD-like phenotypes such as decrease of synapses and neuronal death; this suggests existence of a pathogenic mechanism of AD independent from APP (Non-Patent Document No. 1).
On the other hand, Eph receptor A7 (EphA7) is a member of the receptor tyrosine kinase family, and EphA family is a group of molecules which regulate the formation and maintenance of synapses (Non-Patent Document No. 2). Therefore, it is believed highly possible that EphA7 is also involved in the formation and maintenance of synapses.
However, it has never been reported to date that EphA7 is a substrate for γ-secretase.    [Non-Patent Document No. 1] Saura C A, Choi S Y, Beglopoulos V, Malkani S, Zhang D, Shankaranarayana Rao B S, Chattarji S, Kelleher R J 3rd, Kandel E R, Duff K, Kirkwood A, and Shen J., Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration, Neuron. 2004 Apr. 8; 42(1):23-36.    [Non-Patent Document No. 2] Yamaguchi Y, Pasquale E B. Eph receptors in the adult brain. Curr Opin Neurobiol. 2004 June; 14(3):288-96.